Asymmetrical ester derivatives of 1,4-dihydrophyridine-3,5-dicarboxylic acid

ABSTRACT

The present invention relates to novel asymmetrical esters derived from 1,4-dihydrophyridine-3,5-dicarboxylic acid, of the formula: ##STR1## in which: R 1  represents a C 1  -C 4  alkyl group, R 2  represents a C 1  -C 4  alkyl group, a benzyl group, a benzoyl group or a phenyl group optionally substituted by one or more C 1  -C 4  alkoxy, C 1  -C 4  alkyl, cyano, nitro, hydroxyl or trifluoromethyl groups or by one or more halogen atoms, and R 3  and R 4 , which are identical or different, each represent the hydrogen atom, a nitro group or a chlorine atom, their optical isomers and diastereoisomers and also the corresponding addition salts. 
     These novel esters are useful in therapy, especially as antihypertensives.

FIELD OF THE INVENTION

The present invention relates to novel derivatives of1,4-dihydropyridine-3,5-dicarboxylic acid. It also relates to themethods for their preparation and to their application in therapy.

PRIOR ART

French patent application No. 85-02412, filed in the name of theApplicant Company, describes asymmetrical heterocyclic esters of1,4-dihydropyridine-3,5-dicarboxylic acids which correspond to theformula: ##STR2## in which, in particular, R'₁ is C₁ -C₄ alkyl, n is theinteger 1 or 2, X' and Y' each represent O or S, at least one of thesymbols X' and Y' being different from S, and R"₂ and R"₃ each representthe hydrogen atom, the methyl group or phenyl or halogenophenyl groupsor together form a spirocycloaliphatic group.

These products are indicated as vasodilators and differ from the knownproducts of the prior art especially in their antihypertensive effectsand their effects on the cardiac, femoral and coronary outputs.

OBJECT OF THE INVENTION

The Applicant Company has attempted to optimize the pharmacologicalproperties of these products and has now just found novel1,4-dihydropyridine-3,5-dicarboxylic acid derivatives which differ fromthe products of the above-mentioned Application especially in theirstructure and their activity when administered orally.

DETAILED DISCLOSURE OF THE INVENTION

The novel derivatives according to the invention are selected from thegroup comprising:

(i) the esters corresponding to the general formula: ##STR3## in which:R₁ represents a C₁ to C₄ alkyl group, R₂ represents a C₁ -C₄ alkylgroup, a benzyl group, a benzoyl group or a phenyl group optionallysubstituted by one or more C₁ -C₄ alkoxy, C₁ -C₄ alkyl, cyano, nitro,hydroxyl or trifluoromethyl groups or by one or more halogen atoms, andR₃ and R₄, which are identical or different, each represent a hydrogenatom, a nitro group or a chlorine atom;

(ii) their optical isomers and diastereoisomers; and

(iii) the corresponding addition salts.

The groups CH₃, CH₂ CH₃, CH(CH₃)₂, C(CH₃)₃, OCH₃, OCH₂ CH₃, OCH(CH₃)₂and OC(CH₃)₃ may be mentioned in particular among the alkyl and alkoxygroups which are covered by the definition of the groups R₁ and R₂referred to above.

The fluorine, chlorine and bromine atoms may be mentioned among thehalogen atoms which are esuitable according to the invention, thepreferred halogen atom being the chlorine atom.

The preferred groups which R₃ and R₄ form with the phenyl nucleus towhich they are bonded are the 3-nitrophenyl groups and the2,3-dichlorophenyl group.

The compounds of the formula (I) according to the invention can beprepared by two methods:

Method A consists in reacting a benzylideneacetoacetate of the formula:##STR4## in which R₁, R₃ and R₄ are defined as indicated above, with anaminocrotonate of the formula: ##STR5## in which R₂ is defined asindicated above, in accordance with the so-called Hantzsch reaction.

Advantageously, about 1 mol of II is reacted with about 1 mol of III ina polar organic solvent (especially a C₁ -C₄ alkanol such as methanol,ethanol, isopropanol, n-butanol or t-butanol), for 1 to 24 h, at atemperature between room temperature (15°-20° C.) and the refluxtemperature of the reaction medium.

The compounds of the formula II are known substances which can beprepared in accordance with the so-called Knoevenagel reaction, cf. thereview article by G. Jones, Organic Reactions, 15, 204 (1975).

The compounds of the formula III are novel products, the recommendedmethod for their preparation being as follows:

(1) reaction of an alcohol of the formula: ##STR6## in which R₂ isdefined as indicated above, with acetylated Meldrum's acid of theformula: ##STR7## in an aromatic solvent (especially benzene, toluene orxylenes), at a temperature between room temperature (15°-20° C.) and thereflux temperature of the reaction medium, for 0.2 to 4 h, to give anovel ketoester of the formula: ##STR8## in which R₂ is defined asindicated above, and (2) treatment of the resulting derivative of theformula VI with NH₃ in a chlorinated solvent (especially CH₂ Cl₂ orCHCl₃) for 1 to 24 h.

The compounds of the formulae III and VI can be used without priorpurification. Advantageously, they are used after they have beenpurified either by distillation (or recrystallization) or by flashchromatography (column chromatography under pressure) in accordance withthe technique described by W. C. Still et al., J. Org. Chem., 43 (no.14), 2923 (1978).

The ketoesters of the formula VI and the aminocrotonates of the formulaIII, which were prepared as indicated above and are involved in thesynthesis of the compounds according to the invention, have beencollated in the following Tables I and II respectively, without implyinga limitation.

                                      TABLE I                                     __________________________________________________________________________     ##STR9##                                                                                Reaction time          Yield                                       R.sub.2    (hours)                                                                              Solvent                                                                            Method of purification                                                                   (%) NMR spectrum (b)                        __________________________________________________________________________    CH.sub.3   1      toluene                                                                            flash chromatography                                                                     44  1.6-1.85 (4H, m); 2.27                                         toluene/isopropanol/                                                                         (3H, s); 2.29 (3H, s);                                         triethylamine  2.3-2.6 (4H, m); 3.5                                           (95:5:5 v/v/v) (2H, s); 3.6-4.5 (5H, m)                 ##STR10## 2      toluene                                                                            flash chromatography toluene/ethyl acetate (6:4                               v/v)       71  1.6-1.9 (4H, m); 2.25 (3H, s);                                                2.3-2.7 (4H, s); 3.5 (2H, s); 3.55                                            (2H, s); 3.6-4.4 (5H, m); 7.2-7.4                                             (5H, m) (60 MHz)                         ##STR11## 3      toluene                                                                            (a)        100 1.7-2 (4H, m); 2.27 (3H, s);                                                  3.1-3.3 (4H, m); 3.5 (2H, s);                                                 3.6-4.5 (5H, m); 6.8-7 (4H, m)           ##STR12## 3      toluene                                                                            (a)        100 1.7-2 (4H, m); 2.27 (3H, s);                                                  3.0-3.35 (4H, m); 3.5 (2H, s); 3.76                                           (3H, s); 4.0-4.5 (5H, m); 6.7-6                                               (4H, m)                                  ##STR13## 3      toluene                                                                            (a)        94  1.75-2 (4H, m); 2.27 (3H, s);                                                 3.1-3.3 (4H, m); 3.5 (2H, s); 3.83                                            (3H, s); 3.86 (3H, s); 3.7-4.5 (5H,                                           m); 6.4-6.9 (3H, m)                      ##STR14## 2      toluene                                                                            flash chromatography toluene/ethyl acetate (9:1                               v/v)       70  1.8-2.1 (4H, m); 2.3 (3H, s);                                                 3.1-3.4 (4H, m); 3.5 (2H, s);                                                 3.7-4.6 (5H, m); 6.8-7.6 (4H, m)                                              (60 MHz)                                 ##STR15## 0.3    benzene                                                                            chromatography hexane/acetone (7:3                                                       68v)                                                                              1.6-1.95 (4H, m); 2.27 (3H, s);                                               3.4-3.7 (m) and 3.5 (s) (6H);                                                 3.75-4.5 (5H, m); 6.8 (2H, d); 8.1                                            (2H, d)                                  ##STR16## 3      toluene                                                                            (a)        100 1.6-1.9 (4H, m); 2.25 (3H, s);                                                3.3-3.6 (m) and 3.5 (s) (7H);                                                 3.7-4.6 (5H, m); 6.85 (2H, d); 7.45                                           (2H, d) (60 MHz)                         ##STR17## 2      toluene                                                                            (a)        100 1.5-2 (4H, m); 2.27 (3H, s);                                                  3.3-4.6 (m) and 3.5 (s) (6H); 4-4.5                                           (5H, m); 6.8-6.95 (2H, d); 7.35-7.5                                           (2H, d)                                  ##STR18## 1      toluene                                                                            flash chromatography hexane/acetone (7:3                                                 94v)                                                                              1.6-1.9 (4H, m); 2.26 (3H, s);                                                3.4-4.4 (m) and 3.5 (s) (11H);                                                7.2-7.6 (5H, m)                          ##STR19## 2      toluene                                                                            (a)        90  1.7-2.05 (4H, m); 2.28 (3H, s);                                               3.3-3.45 (4H, m); 3.5 (1.8H, s);                                              3.7-4.5 (5H, m); 5.04 (0.1 H, s);                                             6.9-7.5 (4H, m); 11.9 (0.1 H,           __________________________________________________________________________                                          s)                                       Notes:                                                                        (a) without purification                                                      (b) spectrum run at 80 MHz unless indicated otherwise, in CDCl.sub.3,         relative to TMS                                                          

                                      TABLE II                                    __________________________________________________________________________     ##STR20##                                                                    R.sub.2     Reaction time (hours)                                                                    Solvent                                                                              Method of purification                                                                   Yield (%)                                                                           NMR spectrum                   __________________________________________________________________________    CH.sub.3    5          methanol                                                                             flash chromatography                                                                      44   1.6-1.95 (m) and 1.9 (s)                                                      (7H);                                                        toluene/isopropanol/                                                                           2.3 (3H, s); 2.3-2.48 (4H,                                                    m);                                                          triethylamine    3.6-4.4 (5H, m); 4.55 (1H,                                                    s)                                                           (95:5:5 v/v/v)                                   ##STR21##  5          methylene chloride                                                                   (a)         98   1.65-2 (m) + 1.9 (s) (7H);                                                    .4-2.75 (4H, m); 3.55 (2H,                                                    s); 3.6-4.5 (5H, m); 4.6                                                      (1H, s); 7.25-7.4 (5H, m)       ##STR22##  4          chloroform                                                                           (a)        100                                   ##STR23##  3          chloroform                                                                           (a)        100   1.7-2 (m) + 1.9 (s) (7H);                                                     3.1-3.4 (4H, m); 3.76 (3H,                                                    s); 3.9-4.5 (5H, m); 4.54                                                     (1H, s); 6.7-7 (4H, m)          ##STR24##  4          chloroform                                                                           (a)        100   1.75-2 (m) + 1.9 (s) (7H);                                                    -3.3 (4H, m); 3.82 (3H,                                                       s); 3.86 (3H, s); 3.6-4.5                                                     (5H, m); 4.55 (1H, s);                                                        6.4-6.8 (3H, m)                 ##STR25##  12         methylene chloride                                                                   (a)        100   1.8-2.1 (m) + 1.9 (s)                                                         (7H); 3.1-3.4 (4H, m);                                                        3.7-4.45 (5H, m); 4.55                                                        (5H, m); 4.55 (1H, s);                                                        6.8-7.6 (4H, m) (60 MHz)        ##STR26##  2          methylene chloride                                                                   (a) (b)     97   1.6-1.95 (m) + 1.9 (s)                                                        (7H); 3.4-3.7 (m, 4H);                                                        3.8-4.55 (m, 5H); 4.55                                                        (1H, s); 6.8 (2H, d); 8.1                                                     (2H, d)                         ##STR27##  24         methylene chloride                                                                   (a) (c)     77   1.6-1.9 (m) + 1.9 (s)                                                         (7H); 3.3-3.6 (4H, m);                                                        3.7-4.5 (5H, m); 4.55 (1H,                                                    s); 6.85 (2H, d); 7.45                                                        (2H, d) (60 MHz)                ##STR28##  11         chloroform                                                                           (a)        100   1.7-2 (m) + 1.9 (s) (7H);                                                     3.25-3.6 (4H, m); 3.7-4.4                                                     (5H, m); 4.56 (1H, s);                                                        6.8-6.95 (2H, d); 7.35-7.5                                                    (2H, d)                         ##STR29##  12         methylene chloride                                                                   (a)        100 (crude)                                                                         1.55-1.95 (m) + 1.9 (s)                                                       (7H); 3.4-4.4 (9H, m); 4.5                                                    (1H, s); 7.2-7.6 (5H, m)        ##STR30##  12         chloroform                                                                           (a)        100 (crude)                                                                         1.7-2 (m) + 1.9 (s) (7H);                                                     3.2-3.5 (4H, m); 3.7-4.5                                                      (6H, m); 4.56 (1H, s);                                                        6.9-7.5 (4H,                   __________________________________________________________________________                                                   m)                              Notes:                                                                        (a) without purification                                                      (b) melting point: 176° C.                                             (c) melting point: 170-175° C.                                         (d) spectrum run at 80 MHz unless indicated otherwise, in CDCl.sub.3,         relative to TMS                                                          

Method B consists of a ketalization in which a protected or unprotecteddiol of the formula: ##STR31## in which R₁, R₃ and R₄ are defined asindicated above, is reacted with a piperidinone of the formula:##STR32## in which R₂ is defined as indicated above.

The diol of the formula VII can be used in protected form, for examplein the form of a substituted or unsubstituted methyl or ethyl ether, asilylated ether, an ester, a carbonate, an acetal, for example theacetanilide, a cyclopentylidene, cyclohexylidene or benzylidene or acyclic orthoester.

Advantageously, about 1 mol of VII is reacted with about 1 mol of VIIIin a polar organic solvent, for example a C₁ -C₄ alcohol, an aromaticsolvent such as benzene, xylenes or toluene, or mixtures thereof, in thepresence of a mineral acid, for example sulfuric or hydrochloric acid,or an organic acid, for example paratoluenesulfonic or benzenesulfonicacid, at a temperature between room temperature and the refluxtemperature of the reaction medium, for 1 to 12 hours.

The compound of the formula VII can be prepared by a method known perse, especially for opening the dioxolanyl ring of a compound of theformula: ##STR33## in which R₁, R₃ and R₄ are defined as indicated aboveand R'₂ and R'₃ each represent H or a C₁ -C₄ alkyl group, in an acidmedium.

A number of compounds of the formula I according to the invention havebeen collated in the following Table III, without implying a limitation.

                  TABLE III                                                       ______________________________________                                         ##STR34##                                                                    Example                                                                              R.sub.2        R.sub.3  R.sub.4                                                                            M.p. (°C.)                         ______________________________________                                                ##STR35##     3-NO.sub.2                                                                             H     87                                       2                                                                                     ##STR36##     3-NO.sub.2                                                                             H     89                                       3      CH.sub.3       3-NO.sub.2                                                                             H    62 to 76 (a)                              4                                                                                     ##STR37##     3-NO.sub.2                                                                             H    65 to 85 (a)                              5                                                                                     ##STR38##     3-NO.sub.2                                                                             H    65 to 85 (a)                              6                                                                                     ##STR39##     3-NO.sub.2                                                                             H    70 to 95 (a)                              7                                                                                     ##STR40##     3-NO.sub.2                                                                             H     95 to 115 (a)                            6                                                                                     ##STR41##     3-NO.sub.2                                                                             H    70 to 93 (a)                              9                                                                                     ##STR42##     3-NO.sub.2                                                                             H     85 to 108 (a)                            10                                                                                    ##STR43##     3-NO.sub.2                                                                             H    115                                       11                                                                                    ##STR44##     3-NO.sub.2                                                                             H    75 to 80 (a)                              12                                                                                    ##STR45##     3-NO.sub.2                                                                             H    65 to 95 (a)                              13                                                                                    ##STR46##     3-NO.sub.2                                                                             H     62 to 110 (a)                            14                                                                                    ##STR47##     3-NO.sub.2                                                                             H    75 to 85 (a)                              15                                                                                    ##STR48##     3-NO.sub.2                                                                             H    102 to 114 (a)                            16                                                                                    ##STR49##     3-NO.sub.2                                                                             H    80 to 95 (a)                              21                                                                                    ##STR50##     2-Cl     3-Cl 100                                       ______________________________________                                         Notes:                                                                        (a) These products do not have a sharp melting point and melt over the        range indicated.                                                              (b) foam                                                                 

The enantiomers and diastereoisomers can be separated from thecorresponding racemates by a method known per se, especially byfractional crystallization, by resolution or by some other method.

The enantiomers according to the invention can also be prepared by amethod wherein:

(1) a dihydropyridine of the formula: ##STR51## in which R₁, R₃ and R₄are defined as above and the carbon marked * has the R configuration orthe S configuration, is reacted with carbonyldiimidazole, and,

(2) without isolation of the intermediate derivative formed, thereaction medium is reacted with an alcohol of the formula: ##STR52## inwhich R₂ is defined as above and the carbon marked * has the Rconfiguration or the S configuration, to give a compound of the formula:##STR53## in which R₁, R₂, R₃ and R₄ are defined as above and thecarbons marked * have the R configuration or the S configuration, and

(3) the compound of the formula XI is treated in an acid medium to givea compound of the formula: ##STR54## in which R₁, R₂, R₃ and R₄ aredefined as above and the carbons marked * have the R configuration orthe S configuration.

Advantageously, about 1 mol of X is reacted with about 1 mol ofcarbonyldiimidazole in an inert organic solvent (especiallydimethylformamide, dimethylacetamide or dimethyl sulfoxide), for 0.5 to4 h, at a temperature between room temperature (15°-20° C.) and about80° C., about 1 mol of IV' and about 1 mol of a strong organic base(especially 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene or 4-dimethylaminopyridine) are thenadded and the reaction medium is heated at a temperature of betweenabout 40° C. and about 150° C. for 1 to 10 h. The compound of theformula XI is isolated in the conventional way and treated in a strongacid medium (especially N hydrochloric acid), in an organic solvent(especially a ketone), to give an optically active compound of theformula I'.

The compounds of the formula I can be converted to salts by theconventional methods known to those skilled in the art. Preference willbe given in particular to the addition salts obtained by reaction withbiologically acceptable strong acids, for example hydrochloric,hydrobromic, methanesulfonic, nitric or sulfuric acid.

According to the invention, a therapeutic composition is recommendedwhich contains, in association with a physiologically acceptableexcipient, at least one compound selected from the group comprising thederivatives of the formula I above, their enantiomers anddiastereoisomers and their addition salts.

Of course, in a composition of this type, the active principle ispresent in a pharmaceutically effective amount.

According to the invention, it is also recommended to use a substanceselected from the group comprising (i) the derivatives of the formula I,(ii) their enantiomers and diastereoisomers, and (iii) their nontoxicaddition salts, in order to obtain an antihypertensive drug to be usedin human therapy for the treatment of hypertension and cardiacinsufficiencies.

Further advantages and characteristics of the invention will beunderstood more clearly from the following description of preparativeexamples and results of pharmacological tests. These data as a whole donot imply a limitation but are given by way of illustration. In the saidexamples, the R and S configurations are denoted in accordance with thenomenclature rules in Chemical Abstracts.

PREPARATION I Preparation of(8-aza-1,4-dioxa-8-phenylspiro[4,5]decan-2-yl)methyl 3-oxobutanoate

A mixture of 19 g (7.66·10⁻² mol) of(8-aza-1,4-dioxa-8-phenylspiro[4,5]decan-2-yl)methanol, 14.2 g(7.66·10⁻² mol) of acetylated Meldrum's acid (compound of the formula V)and 200 ml of toluene is heated under reflux for 3 hours. The solvent isevaporated off and the crude product obtained is purified by flashchromatography, elution being carried out with a toluene/ethyl acetatemixture (19:1 v/v) and then a hexane/acetone mixture (19:1 v/v). Thisgives 19.8 g (yield: 78%) of the expected product in the form of ayellow oil.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.7-2 (4H, m); 2.26 (3H, s); 3.2-2.45(4H, m); 3.5 (2H, s); 3.6-4.5 (5H, m); 6.7-7.3 (5H, m).

PREPARATION II Preparation of(8-aza-1,4-dioxa-8-phenylspiro[4,5]decan-2-yl)methyl aminocrotonate

19.8 g (5.96·10⁻² mol) of the product obtained in Preparation I aredissolved in 200 ml of methanol. Ammonia gas dried over potassiumhydroxide is bubbled for 2 hours into the solution kept at 0° C. andthen for 4 hours at room temperature. The solvent is evaporated off andthe crude product obtained is purified by flash chromatography, elutionbeing carried out with a hexane/acetone mixture (19:1 v/v) and then ahexane/acetone mixture (9:1 v/v). This gives 15 g (yield: 75%) of theexpected product in the form of a pale yellow oil.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.7-2 (m) and 1.89 (s) (7H); 3.2-3.45(4H, m); 2.5-4.5 (5H, m); 4.55 (1H, s); 6.7-7 (3H, m); 7.2-7.3 (2H, m).

PREPARATION III Preparation of methyl(8-aza-1,4-dioxa-8-phenylspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Example 2

A mixture of 14.7 g (4.44·10⁻² mol) of the product obtained inPreparation II and 11 g (4.44·10⁻² mol) of methyl3-nitrobenzylideneacetylacetate in 300ml of tertiary butanol is heatedunder reflux for 4 hours. The solvent is evaporated off and the crudeproduct is purified by flash chromatography, elution being carried outwith a hexane/acetone mixture (19:1 v/v), then a toluene/isopropanolmixture (100:1 v/v) and then a hexane/acetone mixture (8:2 v/v). Thisgives 5.7 g (yield: 25%) of a yellow oil, which solidifies in the formof an amorphous foam melting at 89° C.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.8 (4H, m); 2.36 (6H, s); 3.3 (4H, m);3.5-4.3 (8H, m); 5.11 (1H, s); 5.8 (1H, s); 6.8-8.1 (9H, m).

PREPARATION IV Preparation of methyl(8-aza-1,4-dioxa-8-phenylspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Example 2

2.03 g (0.5·10⁻² mol) of methyl 1,2-dihydroxypropan-3-yl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate aredissolved in 10 ml of methanol, and 0.96 g (0.55·10⁻² mol) ofN-phenylpiperidin-4-one, 20 ml of toluene and 0.3 g ofparatoluenesulfonic acid are then added. The mixture is heated for 3hours under reflux and then brought back to room temperature andhydrolyzed in 100 ml of a saturated aqueous solution of sodiumbicarbonate. The reaction medium is then extracted three times with 30ml portions of ethyl acetate. The organic phases obtained are combinedand washed three times with 20 ml portions of water. The organicsolution obtained is dried over magnesium sulfate and filtered and thesolvent is evaporated off. The oil obtained is purified by flashchromatography, elution being carried out with a toluene/isopropanolmixture (95:5 v/v). This gives 15.5 g (yield: 55%) of the expectedproduct in the form of a yellow foam with characteristics identical tothose of the product obtained in Preparation III.

PREPARATION V Preparation of methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Example 11

2.03 g (0.5·10⁻² mol) of methyl 1,2 -dihydroxypropan-3-yl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate aredissolved in 10 ml of methanol, and 1.15 g (0.55·10⁻² mol) ofN-(4-chlorophenyl)piperidin-4-one, 20 ml of toluene and 0.2 g ofparatoluenesulfonic acid are then added. The mixture is heated for 3hours under reflux and then cooled to room temperature and hydrolyzed in100 ml of a saturated aqueous solution of sodium bicarbonate. Thereaction medium is extracted three times with 30 ml portions of ethylacetate. The organic phases are combined and washed three times with 20ml portions of water and then dried over magnesium sulfate and filteredand the solvent is evaporated off. The oil obtained is purified by flashchromatography, elution being carried out with a toluene/isopropanolmixture (95:5 v/v). This gives 1.7 g (yield: 57%) of the expectedproduct in the form of a crystalline powder which melts at 145°-150° C.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.8 (4H, m); 2.36-2.38 (6H, 2s); 3.26(4H, m); 3.5-4.4 (m) including 3.64 (s) and 3.65 (s) (8H); 5.12 (1H, s);5.85 (1H, s); 6.6-8.1 (8H, m).

PREPARATION VI Preparation of(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl3-oxobutanoate

A mixture of 3.5 g (0.0122 mol) of(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol, 2.95 g(0.0159 mol) of acetylated Meldrum's acid and 100 ml of toluene isheated under reflux for one hour. The solvent is then evaporated off andthe oil obtained is purified by flash chromatography, elution beingcarried out with a toluene/ethyl acetate mixture (8:2 v/v). This gives3.5 g (yield: 78%) of a yellow solid melting at 59° C.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.65-2 (4H, m); 2.27 (3H, s); 3.1-3.4(4H, m); 3.5 (2H, s); 3.6-4.5 (5H, m); 6.83 (2H, d); 7.2 (2H, d).

PREPARATION VII Preparation of(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylaminocrotonate

Ammonia gas dried over potassium hydroxide is bubbled into a mixture of3.5 g (0.95·10⁻² mol) of(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl3-oxobutanoate, 100 ml of dry methylene chloride and 5 g of a 4 Åmolecular sieve at room temperature for 6 h and the reaction medium isthen stirred for 12 hours. The molecular sieve is filtered off and thesolvent is evaporated off. This gives 3.06 g of a crystalline yellowproduct melting at 60° C. (yield: 88%).

NMR spectrum: 80 MHz TMS (CDCl₃) 1.7-2 (m) and 1.91 (s) (7H); 3.1-3.4(4H, m); 3.6-4.5 (5H, m); 4.56 (1H, s); 6.75-6.90 (2H, d); 7.1-7.25 (2H,d).

PREPARATION VIII Preparation of methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Example 11

A mixture of 3.1 g (0.85·10⁻² mol) of(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylaminocrotonate, 2.1 g (0.85·10⁻² mol) of methyl3-nitrobenzylideneacetylacetate and 100 ml of tertiary butanol is heatedunder reflux for eight hours. The solvent is evaporated off and thecrude product obtained is purified by flash chromatography, elutionbeing carried out with a toluene/isopropanol mixture (95:5 v/v) and thena hexane/acetone mixture (8:2 v/v). This gives 1.7 g (yield: 35%) of theexpected product with physical characteristics identical to those of theproduct obtained in Preparation V.

PREPARATION IX Preparation of methyl(8-aza-1,4-dioxa-8-phenylspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Example 12

A mixture of 0.22 g (5·10⁻⁴ mol) of methyl(2,2-dimethyl-1,3-dioxolan-4-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate,0.26 g (1.5·10⁻⁵ mol) of N-phenylpiperidin-4-one, 8 ml of toluene and 35mg of paratoluenesulfonic acid is heated under reflux for 6 h. Thereaction mixture is hydrolyzed in a saturated aqueous solution of sodiumbicarbonate. The medium obtained is extracted with ethyl acetate. Theorganic phases obtained are washed with water, dried over magnesiumsulfate and filtered and the solvent is evaporated off. The crudeproduct obtained is purified by flash chromatography, elution beingcarried out with a toluene/isopropanol mixture (98:2 v/v). This gives0.07 g (yield: 25%) of the expected product with physicalcharacteristics identical to those of the product obtained inPreparation III.

PREPARATION X Preparation of methyl(8-aza-1,4-dioxa-8-(4-hydroxyphenyl)spiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Example 14

If the procedure described in Preparation IV is followed and a mixtureof 6 g (0.015 mol) of methyl 1,2-dihydroxypropan-3-yl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate,1.9 g (0.01 mol) of N-(4-hydroxyphenyl)piperidin-4-one and 0.5 g ofparatoluenesulfonic acid in 30 ml of butanol and 60 ml of toluene isheated under reflux for 11 h, 2.2 g (yield: 38%) of the expected productare obtained in the form of a foam after two successive purifications byflash chromatography, elution being carried out with a hexane/acetonemixture (1:1 v/v).

M.p.=102° to 114° C.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.7-2 (4H, m); 2.37 (6H, s); 3.0-3.3(4H, m); 3.63 and 3.64 (3H, ds); 3.6-4.5 (5H, m); 5.12 (1H, s); 6.08(1H, s); 6.70 and 6.88 (4H, dd); 7.25-8.15 (4H, m).

PREPARATION XI Preparation of methyl(8-aza-1,4-dioxa-8-(4-methylphenyl)spiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Example 15

If the procedure described in Prepration IV is followed and a mixture of2 g (0.005 mol) of methyl 1,2-dihydroxypropan-3-yl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate,1.86 g (0.01 mol) of N-(4-methylphenyl)piperidin-4-one and 0.2 g ofparatoluenesulfonic acid in 20 ml of toluene and 10 ml of butanol isheated under reflux for 24 hours, 2.1 g (yield: 70%) of the expectedproduct, melting over the range from 75° to 85° C., are obtained in theform of a foam after two successive purifications by flashchromatography, elution being carried out with a hexane/acetone mixture(6:4 v/v) and then ether.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.7-1.95 (4H, m); 2.26 (3H, s); 2.35(6H, s); 3.05-3.3 (4H, m); 3.63 (3H, s); 3.6-4.5 (5H, m); 5.12 (1H, s);6.17 (1H, s); 6.8 and 7.07 (4H, dd); 7.2-8.15 (4H, m).

PREPARATION XII Preparation of(8-aza-1,4-dioxa-8-(4-trifluoromethylphenyl)spiro[4,5]decan-2-yl)methyl3-oxobutanoate

A mixture of 4.75 g (0.015 mol) of(8-aza-1,4-dioxa-8-(4-trifluoromethylphenyl)spiro[4,5]decan-2-yl)methanol,3 g (0.016 mol) of acetylated Meldrum's acid (compound of the formula V)and 50 ml of toluene is heated under reflux for two hours. The mixtureis brought back to room temperature and water is added. The organicphase is decanted and then washed with water until the pH of thewashings is neutral, and dried. This gives 6 g of an oil.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.5-2 (4H, m); 2.27 (3H, 2); 3.3-4.6(m)+3.5 (s) (6H); 4-4.5 (5H, m); 6.8-6.95 (2H, d); 7.35-7.5 (2H, d).

PREPARATION XIII Preparation of(8-aza-1,4-dioxa-8-(4-trifluoromethylphenyl)spiro[4,5]decan-2-yl)methylaminocrotonate

6 g (0.015 mol) of the product obtained in Preparation XII are dissolvedin 100 ml of chloroform. Ammonia gas is bubbled into the solution for 3hours and then for a further 8 hours after a molecular sieve has beenadded to the reaction medium. The mixture is filtered and the organicphase obtained is evaporated. This gives 6 g of a solid melting at 122°C.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.7-2 (m)+1.9 (s) (7H); 3.25-3.6 (4H,m); 3.7-4.4 (5H, m); 4.56 (1H, s); 6.8-6.95 (2H, d); 7.35-7.5 (2H, d).

PREPARATION XIV Preparation of methyl(8-aza-1,4-dioxa-8-(4-trifluoromethylphenyl)spiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

A mixture of 6 g (0.015 mol) of the product obtained in Preparation XIIIand 3.7 g (0.015 mol) of methyl 3-nitrobenzylideneacetylacetate intertiary butanol is heated under reflux for 1 hour. The solvent isevaporated off and the crude product is successively purified twice byflash chromatography, elution being carried out with atoluene/isopropanol mixture (9:1 v/v) and then a toluene/isopropanolmixture (19:1 v/v). This gives 2.3 g (yield: 25%) of an oil, whichsolidifies in the form of an amorphous foam melting over the range from65° to 95° C.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.8 (4H, m); 2.36-2.38 (6H, ds); 3.4(4H, m); 3.5-4.5 (m)+3.64 (s)+3.65 (s) (8H); 5.12 (1H, s); 5.76 (1H, s);6.7-8.1 (8H, m).

PREPARATION XV Preparation of methyl(8-aza-8-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Example 16

If the procedure described in Preparation IV is followed starting from4.06 g (10⁻² mol) of methyl 1,2-dihydroxypropan-3-yl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate and2.44 g (10⁻² mol) of N-(2,4-dichlorophenyl)piperidin-4-one, 5.6 g(yield: 90%) of the expected product are obtained, which melts over therange from 80° to 95° C.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.87 (4H, m); 2.39 (6H, s); 3.05 (4H,m); 3.5-4.4 (m) and 3.64 (s) (8H); 5.12 (1H, s); 5.99 (1H, s); 6.95-8.1(7H, m).

PREPARATION XVI Preparation of methyl 1,2-dihydroxypropan-3-yl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate(intermediate involved in Preparation IV above)

11.1 g (2.48·10⁻² mol) of methyl (2,2-dimethyl-1,3-dioxolan-4-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, 50ml of methanol and 50 ml of 1N HCl are introduced into a 250 mlround-bottomed flask. The reaction medium is stirred for 1 h at 15°-20°C. and then neutralized with NaHCO₃. The methanol is evaporated off andthe residue is extracted with 100 ml of ethyl acetate. The ethyl acetatephase is washed with water until the pH of the washings is neutral, andthen dried (over MgSO₄) and filtered and the filtrate is evaporatedunder reduced pressure. The evaporation residue is collected (9.2 g;yield: 91%); this product is in the form of a yellow foam melting at 90°C. and essentially consists of methyl 1,2-dihydroxypropan-3-yl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.73 (1H, s); 2.37 (7H, s); 3.5 (2H,m); 3.6 (3H, s); 3.8 (1H, m); 4.19 (2H, m); 5.1 (1H, s); 6.01 (1H, s);7.3-8.03 (4H, m).

PREPARATION XVII Preparation of(R)-8-aza-1,4-dioxa-8-(4-chlorophenyl)-2-(2-propenyloxymethyl)spiro[4,5]decane

A mixture of 16 g (0.075 mol) of N-(4-chlorophenyl)piperidin-4-one, 1.6g of paratoluenesulfonic acid and 70 ml of anhydrous methanol is heatedunder reflux. When the ketal has been formed, 10 g (0.075 mol) of(S)-3-(2-propenyloxy)propane-1,2-diol are added. The methanol is thendistilled and replaced with toluene. After a reaction time of one hour,the reaction mixture is left to cool to room temperature. It ishydrolyzed in a saturated aqueous solution of sodium bicarbonate. Themedium obtained is extracted with ethyl acetate. The organic phases arewashed with water, dried over magnesium sulfate and filtered and thesolvent is evaporated off. The crude product obtained is purified byflash chromatography, elution being carried out with a hexane/acetonemixture (9:1 v/v). This gives 16 g (yield: 75%) of the pure product withthe following physical characteristics:

NMR spectrum: 80 MHz TMS (CDCl₃) 1.7-2 (4H, m); 3.1-3.4 (4H, m); 3.5-4.5(7H, m); 5.05-5.45 (2H, m); 5.75-6.2 (1H, m); 6.83 (2H, d); 7.2 (2H, d)

Optical rotation: C=0.65 g/100 ml (methanol) [α]_(D) ²⁰ =-8.2

Melting point: 40° C.

PREPARATION XVIII Preparation of(S)-8-aza-1,4-dioxa-8-(4-chlorophenyl)-2-(2-propenyloxymethyl)spiro[4,5]decane

If a procedure analogous to the previous preparation is followed and(R)-3-(2-propenyloxy)propane-1,2-diol is reacted with the ketal, theexpected product is obtained, its NMR spectrum and melting point beingidentical to those of the product obtained in the previous preparation.

Optical rotation: C=0.65 g/100 ml (methanol) [α]_(D) ²⁰ =+10.3.

PREPARATION XIX Preparation of(R)-8-aza-2-hydroxymethyl-1,4-dioxa-8-(4-chlorophenyl)spiro[4,5]decane

20.1 g (0.062 mol) of the product obtained in Preparation XVII aredissolved in a mixture of 450 ml of acetone and 45 ml of water. Amixture of 15.7 g of mercuric oxide and 18.5 g of mercuric chloride in110 ml of an acetone/water mixture (10:1 v/v) is added dropwise at roomtemperature. The reaction medium is stirred for one hour and thenfiltered on Celite® and the solvent is evaporated off. The residue issubsequently taken up in ether and then washed with an aqueous solutionof potassium iodide. The ether is evaporated off. The crude productobtained is purified by flash chromatography, elution being carried outwith a toluene/ethyl acetate mixture (8:2 v/v). This gives 16.3 g(yield: 93%) of the expected product in the form of white crystals.

Optical rotation: C=0.46 g/100 ml (methanol) [α]_(D) ²⁰ =-4.0

Melting point: 125° C.

PREPARATION XX Preparation of(S)-8-aza-2-hydroxymethyl-1,4-dioxa-8-(4-chlorophenyl)spiro[4,5]decane

If a procedure analogous to the previous preparation is followedstarting from the product obtained in Preparation XVIII, the expectedproduct is obtained with the following physical characteristics:

Optical rotation: C=0.46 g/100 ml (methanol) [α]_(D) ²⁰ =+4.9

Melting point: 130° C.

PREPARATION XXI Preparation of methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylN-(ethoxymethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate(R-(R*,S*))

2.925 g (0.0075 mol) of(R)-N-(Ethoxymethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarboxylpyridine-5-carboxylicacid and 1.34 g (0.0082 mol) of carbonyldiimidazole are dissolved in 50ml of dimethylformamide. The mixture is heated at 40° C. for one hour.2.13 g (0.0075 mol) of the product obtained in Preparation XX and 1.12ml (0.0075 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are then added tothe reaction medium. The mixture is heated to 100° C. After 2 hours, themixture is left to cool and then poured into 100 ml of water. The mediumis extracted 3 times with 30 ml of ethyl acetate. The organic phasesobtained are washed twice with 10 ml of water, dried over magnesiumsulfate and filtered and the solvent is evaporated off. The crudeproduct obtained is purified by flash chromatography, elution beingcarried out with a toluene/isopropanol mixture (97:3 v/v). This gives4.8 g (yield: 98%) of an oil.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.23 (3H, t); 1.65-2 (4H, m); 2.56 (6H,s); 3.05-3.35 (4H, m); 3.47 (2H, q); 3.69 (3H, s, s); 3.50-4.40 (5H, m);4.86 (2H, s); 5.19 (1H, s); 6.83 (2H, d); 7.19 (2H, d); 7.25-7.75 (2H,m); 7.8-8.1 (2H, m).

PREPARATION XXII Preparation of methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate(R-(R*,S*))

Example 17

4.9 g (0.0075 mol) of the product obtained in Preparation XXI aredissolved in 120 ml of acetone, 25 ml of N hydrochloric acid and 10 mlof water. The mixture is stirred at room temperature for 8 hours. Thereaction medium is poured into 200 ml of an aqueous solution of sodiumbicarbonate. Extraction is carried out 3 times with 50 ml of ethylacetate. The organic phases are washed twice with 20 ml of water anddried over magnesium sulfate and the solvent is evaporated off. Thecrude product obtained is purified on a chromatography column, elutionbeing carried out with ether. This gives 3 g (yield: 67%) of theexpected product melting at 171° C.

NMR spectrum: 500 MHz TMS (CDCl₃) 1.82 (4H, m); 2.38 (6H, d); 3.26 (4H,m); 3.66 (3H, s); 3.73 (1H, m); 4.05 (1H, m); 4.10 (2H, m); 4.32 (1H,m); 5.11 (1H, s); 5.87 (1H, s); 6.85 (2H, m); 7.19 (2H, m); 7.37 (1H,m); 7.66 (1H, m); 8.00 (1H, m); 8.10 (1H, m)

Optical rotation: C=0.5 g/100 ml (methanol) [α]_(D) ²⁰ =+29.2.

PREPARATION XXIII Preparation of methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate(S-(R*,R*))

Example 18

If a procedure analogous to Preparations XXI and XXII is followedstarting from(R)-N-(ethoxymethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylicacid and the product obtained in Preparation XIX, the expected productis obtained, which melts at 175° C.

NMR spectrum: 500 MHz TMS (CDCl₃) 1.80 (4H, m); 2.37 (6H, d); 3.25 (4H,m); 3.85 (1H, m); 3.64 (3H, s); 3.97 (1H, m); 4.10 (2H, m); 4.33 (1H,m); 5.10 (1H, s); 5.83 (1H, s); 6.85 (2H, d); 7.20 (2H, d); 7.38 (1H,m); 7.65 (1H, m); 8.00 (1H, m); 8.10 (1H, m) Optical rotation: C=0.46g/100 ml (methanol) [α]_(D) ²⁰ =+14.6.

PREPARATION XXIV Preparation of methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate(S-(R*,S*))

Example 19

If a procedure analogous to Preparations XXI and XXII is followedstarting from(S)-N-(ethoxymethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylicacid and the product obtained in Preparation XIX, the expected productis obtained, which melts at 151°-154° C.

NMR spectrum: 500 MHz TMS (CDCl₃) 1.81 (4H, m); 2.38 (6H, d); 3.26 (4H,m); 3.66 (3H, s); 3.73 (1H, m); 4.05 (1H, m); 4.10 (1H, m); 4.32 (1H,m); 5.11 (1H, s); 5.86 (1H, s); 6.84 (2H, m); 7.19 (2H, m); 7.37 (1H,m); 7.66 (1H, m); 7.99 (1H, m); 8.10 (1H, m) Optical rotation: C=0.5g/100 ml (methanol) [α]_(D) ²⁰ =-23.0.

PREPARATION XXV Preparation of methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate(R-(R*,R*))

Example 20

If a procedure analogous to Preparations XXI and XXII is followedstarting from(S)-N-(ethoxymethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylicacid and the product obtained in Preparation XX, the expected product isobtained, which melts at 176°-179° C.

NMR spectrum: 500 MHz TMS (CDCl₃) 1.80 (4H, m); 2.37 (6H, d); 3.25 (4H,m); 3.59 (1H, m); 3.65 (3H, s); 3.97 (1H, m); 4.12 (2H, m); 4.33 (1H,m); 5.10 (1H, s); 5.87 (1H, s); 6.84 (2H, m); 7.17 (2H, m); 7.38 (1H,m); 8.00 (1H, m); 8.10 (1H, m)

Optical rotation: C=0.4 g/100 ml (methanol) [α]_(D) ²⁰ =-10.9.

PREPARATION XXVI Preparation of methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate

Example 21

If the procedure described in Preparation VIII is followed and a mixtureof 2.73 g (0.01 mol) of methyl 2,3-dichlorobenzylideneacetylacetate,3.66 g (0.01 mol) of(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylaminocrotonate and 30 ml of t.butanol is heated under reflux for onehour, 2.6 g (yield: 42%) of the expected product melting at 100° C. areobtained after a first purification by flash chromatography, elutionbeing carried out with an ether/hexane mixture (1:1 v/v) and then asecond purification by flash chromatography, elution being carried outwith ether, and after recrystallization from ethanol.

NMR spectrum: 80 MHz TMS (CDCl₃) 1.77 (4H, m); 2.31 (6H, d); 3.25 (4H,m); 3.40-4.40 (5H, m); 3.60 (3H, s); 5.44 (1H, s); 5.74 (1H, s); 6.80(2H, d); 7.13 (2H, d); 7.00-7.40 (3H, m).

A number of products obtained by the procedure described in PreparationIII have been collated in Table IV below. The solvent used is tertiarybutanol and the reaction temperature is the reflux temperature of thereaction medium. The table indicates the weight of the reactants, thereaction time, the method of purification used, the resulting weight ofthe product of the formula I according to the invention, the yield ofthe reaction and also the NMR spectrum of the expected product.

                                      TABLE IV                                    __________________________________________________________________________               Nitrobenzylidene-         Weight                                      Aminocrotonate                                                                        acetoacetate II                                                                        Time             obtained                                                                           Yield                               Ex.                                                                              III (g) (g)      (hours)                                                                           Method of purification                                                                     (g)  (%) NMR spectrum                    __________________________________________________________________________    1  2.5     1.8      2.5 4 × flash chromatography                                                             2.1  50  1.7 (4H, m); 2.5                                        toluene/ethyl acetate (m) + 2.36 (s)                                          (8:7 v/v)             (10 H); 3-4.3 (m) +                                     toluene/isopropanol   3.6 (s) + 3.5                                           (19:1 v/v)            (s) (10 H); 5.1 (1H,                                    toluene/isopropanol   s); 6.0 (1H, s);                                        (9:1 v/v)             7.2-8.08 (9H, m)                                        toluene/ethyl acetate/                                                        triethylamine (80:5:5                                                         v/v/v)                                                3  5.2     4.8      4   2 × flash chromatography                                                             3.9  40  1.76 (4H, m); 2.49                                      chloroform/methanol   (m) + 2.34 (s) +                                        (50:1 v/v)            2.3 (s) (13H); 3.65                                     toluene/isopropanol/  (3H, s); 3.5-4.4                                        triethylamine (190:10:1                                                                             (5H, m); 5.11 (1H,                                      v/v/v)                s); 6.06 (1H, s);                                                             7.2-8.08 (4H, m)                4  6.4     4.4      1   flash chromatography                                                                       6    56  1.83 (4H, m); 2.36                                      hexane/acetone        (6H, s); 3.16 (4H,                                      (7:3 v/v)             m); 3.63 (3H, s);                                                             3.64 (3H, s); 3.7                                                             (3H, s); 3.5-4.4                                                              (5H, m); 5.12 (1H,                                                            s); 5.89 (1H, s);                                                             6.7-8.1 (8H, m)                 5  7       4.4      1   flash chromatography                                                                       2.5  22  1.85 (4H, m); 2.36                                      hexane/acetone        and 2.38 (6H, ds);                                      (7:3 v/v)             3.17 (4H, m); 3.5-                                                            4.4 (m) + 3.64 (s) +                                                          3.83 (s) + 3.87 (s)                                                           (14H); 5.12 (1H, s);                                                          5.85 (1H, s); 6.4-                                                            8.1 (7H, m)                     6  9       6.5      1   2 × flash chromatography                                                             2.5  18  1.8 (4H, m); 2.36                                       hexane/acetone        and 2.38 (6H, ds);                                      (7:3 v/v)             3.2 (4H, m); 3.5-                                       ether                 4.5 (m) + 3.60 and                                                            3.65 (ds) (8H); 5.11                                                          (1H s); 5.9 (1H, s);                                                          6.8-8.1 (8H, m)                 7  15.4    10.5     12  3 × flash chromatography                                                             3.3  13  1.66 (4H, m); 2.33                                      hexane/acetone        and 2.35 (6H, ds);                                      (7:3 v/v)             3.5-4.2 (m) + 3.6                                       toluene/isopropanol   (s) (12H); 5.1 (1H,                                     (20:1 v/v)            s); 6.2 (1H, s);                                        hexane/acetone        7.3-8.1 (9H, m)                                         (6:4 v/v)                                             8  10.46   7.2      10  4 ×  flash chromatography                                                            3.7  22  1.9 (4H, m); 2.37                                       toluene/isopropanol   and 2.39 (6H, ds);                                      (98:2 v/v)            3.28 (4H, m); 3.5-                                      toluene/isopropanol   4.5 (m) + 3.64 (ds)                                     (97:3 v/v)            (8H); 5.19 (1H, s);                                     toluene/isopropanol   5.95 (1H, s); 7-8.1                                     (97:3 v/v)            (8H, m)                                                 ether/acetone                                                                 (1:1 v/v)                                             9  6       3.96     4   3 × flash chromatography                                                             4.1  42  1.78 (4H, m); 2.36                                      toluene/isopropanol   and 2.39 (6H, ds);                                      (98:2 v/v)            3.2-4.2 (12H, m);                                       toluene/isopropanol   5.12 (1H, s) 6.07                                       (98:2 v/v)            (1H, s); 6.6-8.14                                       ether/acetone         (8H, m)                                                 (1:1 v/v)                                             10 3.1     2.5      3   2 × flash chromatography                                                             3.1  60  1.77 (4H, m); 2.36                                      toluene/isopropanol   and 2.38 (6H, ds);                                      (98:2 v/v)            3.2- 4.4 (m); 3.64                                      ether                 and 3.65 (ds) (12H);                                                          5.11 (1H, s); 6.05                                                            (1H, s); 6.6-8.1                                                              (8H, m)                         12 6       3.7      1   2 × flash chromatography                                                             2.3  25  1.8 (4H, m); 2.36                                       toluene/isopropanol   and 2.38 (6H, ds);                                      (9:1 v/v)             3.4 (4H, m); 3.5-                                       toluene/isopropanol   4.5 (m) + 3.64 and                                      (9:1 v/v)             3.65 (ds) (8H); 5.12                                                          (1H, s); 5.76 (1H,                                                            s); 6.7-8.1 (8H, m)             13 4.4     2.5      1   2 × flash chromatography                                                             1.5  24  1.5-1.95 (4H, m);                                       toluene/ethyl acetate 2.37 (6H, s); 3.1-                                      (10:1 v/v)            3.45 (m, 4H); 3.5-                                      hexane/acetone        4.4 (m) + 3.64 (s)                                      (3:1 v/v)             (8H); 5.13 (1H, s);                                                           6.04 (1H, s); 7-                                                              8.15 (8H,                       __________________________________________________________________________                                                  m)                          

The antihypertensive activity of the products according to the inventionwas demonstrated by oral administration to spontaneously hypertensiverats aged between 16 and 20 weeks. The systolic arterial pressure ismeasured by plethysmography and the heart rate is obtained from thepressure trace. The compounds studied are administered orally. Themaximum antihypertensive effects obtained are collated in Table V below.Unless indicated otherwise, groups of 6 animals were used. Thestatistical significance of the effect after 24 hours is given inbrackets, where * denotes p<0.05, ** denotes p<0.01 and *** denotesp<0.001 according to a variance analysis followed by a Student t test.

The products according to the invention, and nicardipine taken as thereference, were also tested by oral administration to perinephritichypertensive dogs. Mongrel dogs weighing 20 to 25 kg or beagle dogsweighing 10 to 15 kg are rendered hypertensive by enclosing both kidneysin a sheet of cellophane in accordance with the technique described byI. H. Page (J.A.M.A., vol. 113, no. 23, pp 2046-48, 1939). Ten to twelveweeks after the intervention and after the animals have been conditionedfor measurements, the systolic arterial pressure and the heart rate aremeasured using a piezoelectric sensor and an inflatable sleeve(Apelex-BP recorder). The products are administered orally at a dose of3 mg/kg and the parameters are measured 0.5, 1, 2, 4, 6, 8 and 24 hoursafter administration.

By way of example, a drop in the systolic arterial pressure of(44.3±4.8) % was observed for the compound of Example 11, the effectlasting more than 24 hours. Nicardipine causes a drop in systolicarterial pressure of (25.8±17.6) %, the effect lasting no longer than 6hours.

                  TABLE V                                                         ______________________________________                                        Antihypertensive activity in spontaneously                                    hypertensive rats (oral administration)                                              Dose    % Variation in the systolic                                                                      Duration of                                 Product                                                                              (mg/kg) pressure ± standard deviation                                                                 the effect                                  ______________________________________                                        Ex. 1  30       -54.1      ± 5.2  8    to 24                               Ex. 2  10       -44.3      ± 14.8 >24  (*)                                 Ex. 2  30       -51.7      ± 5.8  >24  (***)                               Ex. 3  30       -36.4      ± 13.3 8    to 24                               Ex. 4  30       -37        ± 5    >24  (***)                               Ex. 5  30       -43.6      ± 6.1  >24  (*)                                 Ex. 6   1 (a)   -19.1      ± 10.4 8    to 24                               Ex. 6   3       -29.5      ± 8.0  8    to 24                               Ex. 6  10 (b)   -50.1      ± 3.4  >24  (***)                               Ex. 6  30       -52.6      ± 6.4  >24  (***)                               Ex. 7  30       -43.7      ± 6.6  >24  (*)                                 Ex. 8  30       -19.7      ± 10.8 >24  (*)                                 Ex. 9  30       -30.8      ± 7.7  >24  (**)                                Ex. 10 30       -36.3      ± 4.5  8    to 24                               Ex. 11  3       -36.3      ± 11   >24  (***)                               Ex. 11 10       -48.0      ± 11.1 >24  (***)                               Ex. 11 30       -57.4      ± 6.0  >24  (***)                               Ex. 12 10       -47.8      ± 4.6  >24  (***)                               Ex. 13  3       -29.3      ± 9.1  >24  (*)                                 Ex. 13 10       -43.5      ± 7.0  >24  (***)                               Ex. 14 10       -23.3      ± 12.2 >24  (*)                                 Ex. 15 10       -36.0      ± 11.3 >24  (*)                                 Ex. 16  3       -45.5      ± 7.0  >24  (*)                                 Ex. 17  3       -41.7      ± 2.7  8    to 24                               Ex. 17 10       -46.8      ± 4.3  >24  (***)                               Ex. 18  3       -29.7      ± 13.0 8    to 24                               Ex. 18 10       -44.7      ± 3.1  >24  (***)                               Fx. 19  3       -13.4      ± 7.7  4                                        Ex. 19 10       -32.3      ± 9.0  8    to 24                               Ex. 20  3       -9.0       ± 9.6  6                                        Ex. 20 10       -21.3      ± 9.4  8    to 24                               Ex. 21  3       -27.7      ± 10.6 > 24 (***)                               Ex. 21 10       -41.0      ± 9.3  >24  (**)                                nicardi-                                                                             30       -46.2      ± 6.8  8    to 24                               pine                                                                          nicardi-                                                                             10       -43.7      ± 4.7  4    to 6                                pine                                                                          ______________________________________                                         Notes:                                                                        (a): mean of 5 animals                                                        (b): mean of 4 animals                                                   

What is claimed is:
 1. An asymmetrical heterocyclic ester derivative of1,4-dihydropyridine-3,5-dicarboxylic acid, which is selected from thegroup comprising:(i) the esters corresponding to the formula: ##STR55##in which: R₁ represents a C₁ -C₄ alkyl group, R₂ represents a C₁ -C₄alkyl group, a benzyl group, a benzoyl group or a phenyl groupoptionally substituted by one or more C₁ -C₄ alkoxy, C₁ -C₄ alkyl,cyano, nitro, hydroxyl or trifluoromethyl groups or by one or morehalogen atoms, and R₃ and R₄, which are identical or different, eachrepresent a hydrogen atom, a nitro group or a chlorine atom; (ii) theiroptical isomers and diastereoisomers; and (iii) the correspondingaddition salts.
 2. A derivative according to claim 1, wherein R₂ is CH₃,CH₂ C₆ H₅, COC₆ H₅, C₆ H₅, 4-methoxyphenyl, 3,4-dimethoxyphenyl,4-fluorophenyl, 2-cyanophenyl, 4-cyanophenyl, 4-nitrophenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl,2,4-dichlorophenyl, 4-hydroxyphenyl or 4-methylphenyl.
 3. A derivativeaccording to claim 1, wherein R₃ and R₄ form the 3-nitrophenyl group orthe 2,3-dichlorophenyl group with the phenyl nucleus to which they arebonded. 4.Methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate. 5.Methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate(R-(R*,S*)). 6.Methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate(S-(R*,R*)). 7.Methyl(8-aza-8-(4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate.8.Methyl(8-aza-8-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate. 9.A therapeutic composition which contains, in association with aphysiologically acceptable excipient, at least one compound selectedfrom the group comprising the derivatives of the formula I according toclaim 1, their enantiomers and diastereoisomers and the correspondingaddition salts.
 10. A method of treatment of hypertension and cardiacinsufficiency, which comprises administering to a human being in need ofsuch a treatment an effective antihypertensive amount of a compoundselected from the group consisting of(i)1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid esters of theformula I according to claim 1; (ii) optical isomers anddiastereoisomers thereof; and (iii) non-toxic addition salts thereof.